title: The common African American polymorphism SCN5A-S1103Y interacts with mutation SCN5A-R680H to increase late Na current.
abstract: The common polymorphism SCN5A-S1103Y (∼13% allelic frequency in African Americans) is a risk factor for arrhythmia, sudden unexplained death (SUD), and sudden infant death syndrome. Prompted by a case of autopsy-negative SUD in a 23-year-old African American man who collapsed while playing football, we hypothesized that S1103Y interacted with other SCN5A variants to pathologically modify sodium current (I(Na)). Mutational analysis of arrhythmia-associated genes in the victim revealed the variants SCN5A-R680H and SCN5A-S1103Y. These variants were made both separately and in the same cDNA construct of the alternative splice variant backgrounds (SCN5A-Q1077del and Q1077) and expressed in HEK293 cells. In the most abundant SCN5A-Q1077del, late I(Na) for S1103Y alone was not significantly different from wild type (WT). However, late I(Na) for R680H, R680H+S1103Y (coexpressed), and R680H/S1103Y (on the same cDNA) was increased 2.1-, 3.4-, and 3.6-fold, respectively, compared with WT. Intracellular acidosis (pH 6.7) increased late I(Na) for S1103Y, R680H, R680H+S1103Y, and R680H/S1103Y by 2.2-, 2.4-, 5.0-, and 5.5-fold, respectively, compared with WT at pH 6.7. Expression in the less abundant SCN5A-Q1077 showed no increased late I(Na). This is the initial report of a functional interaction for the common polymorphism S1103Y with another mutation in the major transcript Q1077del of SCN5A. The "double hit" and environmental factor of acidosis may have converged to cause arrhythmic sudden death in this case.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, Wisconsin 53792, USA.
authors.forename: Jianding
authors.initials: J
authors.lastname: Cheng
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Bi-Hua
authors.initials: BH
authors.lastname: Tan
authors.forename: Carmen R
authors.initials: CR
authors.lastname: Valdivia
authors.forename: Stacie
authors.initials: S
authors.lastname: Kroboth
authors.forename: Bin
authors.initials: B
authors.lastname: Ye
authors.forename: Craig T
authors.initials: CT
authors.lastname: January
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
mesh_terms: D001741:Black or African American / Q000235:genetics*; D001145:Arrhythmias, Cardiac / Q000235:genetics; D001483:Base Sequence; D004252:DNA Mutational Analysis; D003645:Death, Sudden / Q000208:ethnology; D005787:Gene Frequency; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011110:Polymorphism, Genetic; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D012964:Sodium